TUMOR-ASSOCIATED ADIPOCYTES, REDOX STATE OF ADIPOSE TISSUE AND MICROMETASTASIS IN GASTRIC CANCER PATIENTS

Abstract

It is well known that a number of tumors (such as gastric, breast, rectal, ovarian cancers etc.) deve­lop in pla­ces of anatomical accumulation of adipose tissue (AT). The modified redox state of the tumor is a factor that dama­ges the mitochondria of adipocytes and reprogramms them into tumor-associated adipocytes (TAAs) that are characterized by pro-oncogenic properties. TAAs are an important source of adipokines and energy supply for the tumor, so studying the mecha­nisms of cellular and meta­bolic symbiosis of adi­pocytes and tumor cells opens up a new therapeutic and dia­gnostic possibi­lities. In parti­cular, they include prediction of the course of micrometastasis taking into account the amount of TAAs, which will allow to develop an individua­lized antitumor therapy for patients with a minimal residual disease (MRD) and overweight. Objective: to identify interrelations between the amount of TAAs and body mass index (BMI), clini­cal and pathological characteristics, gene­ration rate of superoxide radicals (SR) and the activity of gelatina­ses (matrix metalloproteinases-2 and -9) in tumor associated adipose tissue (TAAT), the amount of disseminated tumor cells (DTCs) in the bone marrow (BM) and life expectancy of patients with gastric cancer (GC). Me­thods: immunocyto- and immunohistochemistry, zimo­graphy, NMR-spectroscopy, statistical analysis (Student’s t-test, Spearman’s rank correlation analysis, Kaplan — Me­ier’s survival analysis). Results: a reliable correlation was found between the amount of TAAs in the tumor and the BMI of the patients with GC (rho = 0.41; p = 0.032). The content of TAAs increases with the growth of tumor size in patients with pT4 category in 1.3 times (p < 0.05), which is higher than in the tumors of patients with pT1. Both regio­nal and remote metastases revealed significantly more TAAs in tumors than in case of the absence of metastases. People with obesity and GC live reliably longer than patients with normal weight. Age of patients affects survival only in the presence of obesity: elderly patients live less than patients of middle age. A large number of TAAs in the tumor are associated, on the one hand, with a high rate of SR generation and activity of gelati­nases in the TAAT, and on the other, with distant metastasis of GC. For patients with M1 category, 83% and 64%, respectively, have higher rates of SR and total activity of gelatinases in TAAT, and a 30% increase in TAAs in the tumor than in patients of the M0 category. For patients without clinically detectable metastases (category M0), a signifi­cantly higher amount of TAAs in the presence of DTC in the BM is characteristic of their absence. Patients with less than 26.5% of TAAs in the tumor live reliably longer and have a 2.9-times lower risk of adverse illness pared to patients whose tumors had TAAs higher than 26.5%. For the group of patients with the existing DTCs in the BM, no reliable dependence of survival on the values of the amount of TAAs (p = 0.6203) was detected, but this dependence was found for patients without micrometastases (p = 0.005). Conclusions: dysfunctional AT is a modi­fier of tumor’s microenvironment and a factor of the formation of its aggressive phenotype. The amount of TAAs is associated with tumor growth, its regional and distant metastasis, deposition of the DTCs in the areas of distant metastasis and can be used to control the formation of MRD and the flow of GC in patients with overweight.